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Disorders of puberty can profoundly impact physical and psychosocial well-being. Precocious puberty is pubertal onset before eight years of age in girls and before nine years of age in boys. Patients with early isolated pubertal changes, prepubertal linear growth, and no worrisome neurologic symptoms typically have a benign pattern of development and should be monitored in the appropriate clinical context. Among patients with true precocious puberty, or full activation of the hypothalamic-pituitary-gonadal axis, most girls have an idiopathic etiology, whereas it is commonly due to identifiable pathology on imaging in boys. History and physical examination should be followed by measurements of serum follicle-stimulating hormone, luteinizing hormone, and testosterone (boys) or estradiol (girls); thyroid function testing; and bone age radiography. Brain magnetic resonance imaging should be performed in girls younger than six years, all boys with precocious puberty, and children with neurologic symptoms. Delayed puberty is the absence of breast development in girls by 13 years of age and absence of testicular growth to at least 4 mL in volume or 2.5 cm in length in boys by 14 years of age. Constitutional delay of growth and puberty is a common cause of delayed puberty; however, functional or persistent hypogonadism should be excluded. History and physical examination should be followed by measurements of serum follicle-stimulating hormone, luteinizing hormone, and testosterone (boys) or estradiol (girls); and bone age radiography. Abnormal growth velocity necessitates assessment of serum thyroid function, prolactin, and insulinlike growth factor I. Boys 14 years and older and girls 13 years and older may benefit from sex steroid treatment to jump-start puberty. Referral to a pediatric endocrinologist may be warranted after the initial evaluation.

Puberty is a developmental stage characterized by physical and psychosocial maturation. Abnormal pubertal timing can adversely affect a child's physical and psychosocial well-being and may be caused by a range of generally benign or pathologic etiologies. Physicians must identify which findings are suitable for surveillance over time and which suggest treatable underlying pathology.

In patients with precocious puberty, brain magnetic resonance imaging should be performed in girls younger than six years, all boys, and children with neurologic symptoms to evaluate for a central nervous system lesion.

In patients with precocious puberty, brain magnetic resonance imaging should be performed in girls younger than six years, all boys, and children with neurologic symptoms to evaluate for a central nervous system lesion.

The physical changes of puberty are a result of gonadal sex hormone production, the start of which (gonadarche) indicates pubertal onset. Gonadarche is triggered by the pulsatile release of gonadotropin-releasing hormone, which activates the hypothalamic-pituitary-gonadal (HPG) axis.1–3 Adrenarche (i.e., adrenal androgen production leading to pubic and axillary hair, body odor, and mild acne) is a separate but usually concurrent process and does not in itself indicate true pubertal onset in boys or girls.4–7

In girls, increased ovarian estradiol secretion causes breast development at a mean age of 10 years (range: eight to 12 years). Menarche typically follows 2.5 years after the onset of breast development, at an average age of 12.5 years (range: nine to 15 years).1–5 In boys, testicular enlargement to at least 4 mL in volume or 2.5 cm in length is the first sign of true puberty and occurs at an average age of 11.5 years (range: 9.5 to 14 years).1–4,8–13 Physical changes are described using sexual maturity ratings (Table 11–5,9,14and Table 21–5,9,14), such as Tanner stages, and are affected by body habitus and demographic factors.1–5,12,14

Linear growth velocity is about 5 cm per year from four years of age to puberty with a nadir before the pubertal growth spurt. Girls achieve peak height velocity during sexual maturity ratings 2 and 3 (mean: 8.3 cm per year, age 11 or 12 years) and boys during sexual maturity ratings 3 and 4 (mean: 9.5 cm per year, age 13 or 14 years). On average, girls complete linear growth at 15 years of age and boys at 17 years of age. After menarche, girls grow an average of 7 cm.1–4,14–18

PRECOCIOUS PUBERTY

Precocious puberty is diagnosed when secondary sexual characteristics are identified in girls younger than eight years and boys younger than nine years.5,6 Data suggest a trend toward early pubertal development. Approximately 20% of black girls and 5% to 10% of white girls seven to eight years of age in the United States have glandular breast development, particularly if obese.19–23 Eight years of age can be considered a reasonable cutoff for evaluation in girls.5,6 Because of more frequent pathology in boys with precocious puberty than girls, all pubertal boys younger than nine years should be fully evaluated.5,6,24

DELAYED PUBERTY

Puberty is considered delayed when there are no signs of breast development by 13 years of age in girls or testicular enlargement by 14 years of age in boys.5,7,25 Clinicians should suspect pubertal delay if there is halting or regression of pubertal development. In girls with initial pubertal changes, absence of menarche by 15 years of age is also concerning.

HISTORY

The clinician should inquire about the onset and progression of body odor, acne, breast or testicular development, and pubic and axillary hair. Current or previous therapies, including chemotherapy, radiation therapy, or exogenous sex steroids, may indicate the underlying etiology. Neurologic symptoms may reveal intracranial pathology. For delayed puberty, a history suggestive of underlying chronic disease (e.g., fatigue, pain, abnormal stools), nutrition and exercise patterns, poor psychosocial functioning, cryptorchidism, anosmia [i.e., in Kallmann syndrome]) is important.

Growth patterns, such as constitutional delay, may be familial. Thus, family history should include pubertal timing, especially the mother's age of menarche and father's age of reaching adult height.7,9

Table 31–6,9and Table 41–5,7,8 summarize history and physical examination findings in the evaluation of early and delayed puberty.

PHYSICAL EXAMINATION

Height, weight, and body mass index should be plotted on growth curves, and the height velocity should be calculated.3,23 Target height (midparental height) can be determined using the following equation: [mother's height + father's height + 13 cm in boys or − 13 cm in girls] ÷ 2.18,26 A target height differing from the projected height, as established by extending the growth curve to adulthood or bone age radiography, by approximately more than 10 cm may suggest a pathologic condition.26 Because of the effects of sex steroids on epiphyseal maturation, patients with precocious puberty may present with relatively tall stature (leading to shorter adult height), and those with delayed puberty may present with short stature.26

The patient's sexual maturity rating should be noted, as well as the amounts of acne and axillary and facial hair. In boys, determining the location, consistency, and size of the testes can evaluate for cryptorchidism, malignancy, or Klinefelter syndrome (firm testes), and help determine pubertal staging. In girls, dull pink vaginal mucosa suggests estrogen exposure; virilization (e.g., clitoromegaly) should be excluded.4–7,9,27

The thyroid, abdomen, and neurologic system should be examined for evidence of thyroid or gastrointestinal disease or intracranial pathology. Any dysmorphic features or café au lait spots may suggest Turner or McCune-Albright syndrome.4–7,9,27

Multiple café au lait spots and fibrous dysplasia of bones, ovarian enlargement or testicular abnormalities on ultrasonography; may have menstrual bleeding before other development

Referral to a pediatric endocrinologist for multisystem treatment and surveillance

Ovarian or testicular tumor

May be apparent on physical examination or imaging and accompanied by elevated serum testosterone or estradiol; human chorionic gonadotropin–secreting germ cell tumors activate testes in boys; may occur outside of the gonads

Treatment of the tumor; ovarian tumor should be differentiated from a benign ovarian cyst

*—Pubertal development before 8 years of age in girls or 9 years of age in boys. Rare conditions, such as human chorionic gonadotropin–secreting tumors, Prader-Willi syndrome, and genetic mutations of the LH receptor and kisspeptin 1 gene, are not included in this table.

Multiple café au lait spots and fibrous dysplasia of bones, ovarian enlargement or testicular abnormalities on ultrasonography; may have menstrual bleeding before other development

Referral to a pediatric endocrinologist for multisystem treatment and surveillance

Ovarian or testicular tumor

May be apparent on physical examination or imaging and accompanied by elevated serum testosterone or estradiol; human chorionic gonadotropin–secreting germ cell tumors activate testes in boys; may occur outside of the gonads

Treatment of the tumor; ovarian tumor should be differentiated from a benign ovarian cyst

*—Pubertal development before 8 years of age in girls or 9 years of age in boys. Rare conditions, such as human chorionic gonadotropin–secreting tumors, Prader-Willi syndrome, and genetic mutations of the LH receptor and kisspeptin 1 gene, are not included in this table.

ISOLATED PUBERTAL CHANGES

Premature thelarche, defined by isolated glandular breast tissue on palpation, should be differentiated from lipomastia (isolated fatty breast tissue), which is common in obese children.21 To differentiate these conditions, clinicians may examine the patient in the supine position, thereby making the breasts less prominent, to determine presence or absence of glandular tissue under the areolae. Isolated prepubertal vaginal bleeding not caused by trauma, abuse, a foreign body, infection, or an exceedingly rare tumor is usually benign.6,28

Premature adrenarche, driven by adrenal androgens rather than activation of the HPG axis, leads to slowly progressive appearance of pubic and axillary hair, body odor, sweating, and/or mild acne without change in linear growth velocity or enlargement of the testes, penis, breasts, ovaries, or clitoris. Dehydroepiandrosterone sulfate may be at a pubertal level (i.e., slightly elevated for the patient's chronologic age), whereas estradiol, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) remain at prepubertal levels.5,6,9 Less than 5% of patients have an elevated 17-hydroxyprogesterone level, suggesting mild nonclassic congenital adrenal hyperplasia, which does not usually require treatment. Thus, laboratory evaluation for such isolated findings may be delayed.6 Deferring laboratory tests also applies in cases of fine, sparse pubic hair growth that sometimes occurs in infancy.6

Patients with early isolated pubertal changes, prepubertal linear growth, and no worrisome neurologic symptoms typically have a benign pattern of development, necessitating only surveillance over three to six months to evaluate for progression.3–6,9,29 Laboratory or bone age assessment may be deferred initially. Notably, bone age advancement by two standard deviations has low predictive value in differentiating benign pubertal variants from concerning causes of precocious puberty.6,30

Gynecomastia, or estrogen-mediated glandular breast tissue, is common in pubertal boys. Evaluation for chronic disease; hyperprolactinemia; testicular or adrenal neoplasm; use of prescription, recreational, or performance-enhancing drugs; or hypogonadism (e.g., Klinefelter syndrome) should be initiated if symptoms persist for 18 to 24 months or the patient has no pubertal changes.31

CENTRAL AND PERIPHERAL PRECOCIOUS PUBERTY

Precocious puberty can be characterized by the pathologic location. In central precocious puberty, the HPG axis is activated, resulting in early but normal development, symmetric progression of secondary sexual characteristics, and increasing growth velocity.6,9,32 Central precocious puberty is approximately 10-fold more common in girls than in boys.33 Although usually idiopathic in girls, it can be incited by head trauma, neoplasm, radiation, or genetic conditions.5,6,9 Pathologic causes of central precocious puberty are more common in boys.5,6,9

The initial workup should include measurement of serum FSH, LH, and testosterone in boys or estradiol in girls; thyroid function testing; and bone age radiography (eTable B, Figure 15,6,9). In cases of hyperandrogenic findings, measuring serum dehydroepiandrosterone sulfate and 17-hydroxyprogesterone is indicated. An LH level of more than 0.3 mIU per mL (0.3 IU per L) is the most reliable laboratory finding for central precocious puberty; however, in patients with lower values and high clinical suspicion, a gonadotropin-releasing hormone analogue stimulation test may be warranted.6,34 In cases of diagnostic uncertainty, pelvic ultrasonography can evaluate for increased uterine and ovarian volume expected for age, which may indicate central precocious puberty or a tumor.6

The appropriate timing for neuroimaging to identify central nervous system lesions (e.g., hypothalamic hamartoma, malignancy) in children with precocious puberty is controversial. Girls younger than six years, all boys with precocious puberty, and children with neurologic symptoms such as headache, vision changes, or seizures should be screened with magnetic resonance imaging.5,6,9 Some experts discourage routine neuro-imaging for asymptomatic girls six to eight years of age because pathology requiring treatment is exceedingly rare. With shared decision making, parents can weigh the risks of sedation, intravenous contrast media, and follow-up imaging (leading to anxiety and high cost) against the low likelihood that imaging will show a new central nervous system malignancy (at most 1%).5,6,35

If started early in the course of central precocious puberty, gonadotropin-releasing hormone analogues (e.g., leuprolide [Lupron]) appear to safely prevent premature fusion of growth plates, thereby preserving height potential.36 Because of high annual costs, treatment may be most appropriate if bone age suggests impending short stature or if the patient exhibits aggression (boys) or profound emotionality in response to menses (girls).10,37

Delayed puberty is the absence of breast development by 13 years of age in girls or the absence of testicular growth to at least 4 mL in volume or 2.5 cm in length by 14 years of age in boys.7–9,25,38 Constitutional delay of growth and puberty is the most common cause of delayed puberty in boys (60%) and girls (30%).39,40 It represents an extreme of the normal spectrum of pubertal timing and is a diagnosis of exclusion.39,40 For more than 75% of patients with constitutional delay of growth and puberty, family history may reveal parental pubertal delay.41,42

Other etiologies of delayed puberty are categorized based on gonadotropin levels. In hypergonadotropic hypogonadism, gonadal insufficiency delays puberty and results in elevated levels of FSH and LH. Conditions causing hypergonadotropic hypogonadism can be congenital or acquired and are collectively more common in girls (26%) than in boys (7%) with delayed puberty.7,39

Hypogonadotropic hypogonadism is characterized by low levels of FSH and LH and further classified by the pathology. Functional hypogonadotropic hypogonadism is caused by chronic disease, stress, or inadequate nutrition, and the condition may be transient or reversed. Persistent hypogonadotropic hypogonadism is caused by a congenital abnormality in the HPG axis or an acquired etiology such as a central nervous system tumor, trauma, surgery, or radiation.7,43 Patients with persistent hypogonadotropic hypogonadism require treatment to induce puberty, maintain normal adult levels of sex steroids, and optimize fertility.44eTable C includes the differential diagnosis of delayed or absent puberty.

‡—50% of congenital hypogonadotropic hypogonadism cases; five times more prevalent in boys. It is caused by disrupted migration of gonadotropin-releasing hormone–secreting neurons and the olfactory bulbs.

‡—50% of congenital hypogonadotropic hypogonadism cases; five times more prevalent in boys. It is caused by disrupted migration of gonadotropin-releasing hormone–secreting neurons and the olfactory bulbs.

Initial workup should include measurements of serum FSH, LH, testosterone in boys or estradiol in girls, and bone age radiography (eTable B, Figure 27,8,25,44,45). If abnormal growth velocity is a concern, serum thyroid function, prolactin, and insulinlike growth factor I should be assessed.7 Constitutional delay of growth and puberty can be difficult to distinguish from persistent hypogonadotropic hypogonadism; the latter may be diagnosed at 18 years of age if there is inadequate response to jump-start therapy (which is defined later in this section), and sex steroid replacement is still required.7,45

Diagnostic Approach to Late or Absent Pubertal Development

Bone age indicates the degree of sex steroid effect on bone maturation and future growth potential.7,9 For example, patients with constitutional delay of growth and puberty generally have a delay of more than two years, but this finding is nonspecific.8

Delayed puberty can cause significant psychological distress and low self-esteem.46,47 Girls older than 13 years and boys older than 14 years with possible constitutional delay of growth and puberty or gonadotropin-releasing hormone deficiency may be offered jump-start therapy to induce puberty.5,7,8,25,45 For example, treating boys with testosterone cypionate or enanthate (e.g., 50 to 100 mg intramuscularly per month) and girls with overnight transdermal estradiol (e.g., 6.2 mcg, one-fourth of the 25-mcg 24-hour patch) for three to six months may accelerate attainment of final adult height and generally does not lead to premature epiphysis closure.7,25 If pubertal progression does not occur within four to six months after completing therapy, further evaluation for persistent hypogonadotropic hypogonadism and long-term hormone therapy should be initiated.5,7 Indications for referral to a pediatric endocrinologist are listed in eTable D.

†—Before referral, consider initiating evaluation with measurement of serum luteinizing hormone, follicle-stimulating hormone, and testosterone (boys) or estradiol (girls), and bone age. In those with short stature, serum thyroid-stimulating hormone, prolactin, and insulinlike growth factor I should be measured.

†—Before referral, consider initiating evaluation with measurement of serum luteinizing hormone, follicle-stimulating hormone, and testosterone (boys) or estradiol (girls), and bone age. In those with short stature, serum thyroid-stimulating hormone, prolactin, and insulinlike growth factor I should be measured.

This article updates a previous article on this topic by Blondell, et al.48

Data Sources: A PubMed search was completed using the MeSH function with the key term puberty and at least one of the following qualifiers: early, precocious, delayed, absent, or disorder. The search included meta-analyses, randomized controlled trials, observational studies, and reviews. Nonhuman studies and studies older than 10 years were excluded. The reference lists of included reviews were searched for additional studies of interest. Other searches included Essential Evidence Plus, the Cochrane Database of Systematic Reviews, and the U.S. Preventive Services Task Force website. Search dates: October 1, 2016, to May 21, 2017.

The views expressed in this publication are those of the authors and do not reflect the official policy or position of the Departments of the Army, Navy, or Air Force; the Department of Defense; or the U.S. government.

The Authors

DAVID A. KLEIN, MD, MPH, is an associate program director of the National Capitol Consortium Family Medicine Residency, Fort Belvoir, Va. He is also an assistant professor of family medicine and pediatrics at the Uniformed Services University of the Health Sciences, Bethesda, Md....

JILL E. EMERICK, MD, is a pediatric endocrinologist at Walter Reed National Military Medical Center, Bethesda, Md. She is also an assistant professor of pediatrics at the Uniformed Services University of the Health Sciences.

JILLIAN E. SYLVESTER, MD, is a fellow at the National Capitol Consortium Military Primary Care Sports Medicine Fellowship. At the time this article was written, she was a third-year resident at the National Capitol Consortium Family Medicine Residency.

KAREN S. VOGT, MD, is a program director of the pediatric endocrinology fellowship at Walter Reed National Military Medical Center. She is also an associate professor of pediatrics at the Uniformed Services University of the Health Sciences.

Address correspondence to David A. Klein, MD, MPH, Fort Belvoir Community Hospital, Department of Family Medicine, 9300 DeWitt Loop, Fort Belvoir, VA, 22060 (e-mail: david.a.klein26.mil@mail.mil). Reprints are not available from the authors.

29. Bizzarri C,
Spadoni GL,
Bottaro G,
et al.
The response to gonadotropin releasing hormone (GnRH) stimulation test does not predict the progression to true precocious puberty in girls with onset of premature thelarche in the first three years of life. J Clin Endocrinol Metab.
2014;99(2):433–439.

30. DeSalvo DJ,
Mehra R,
Vaidyanathan P,
Kaplowitz PB.
In children with premature adrenarche, bone age advancement by 2 or more years is common and generally benign. J Pediatr Endocrinol Metab.
2013;26(3–4):215–221.